Ulipristal acetate is a selective progesterone receptor modulator which acts by preventing the effects of the female progesterone hormone. This medicine is available in two brand names in market for the below two different therapeutic uses.
- Esmya® tablets comprising 5 mg ulipristal acetate and therapeutically indicated for Uterine fibroids. It is used for the treatment of moderate to severe symptoms (heavy or painful periods) caused by uterine fibroids in adult women of reproductive age.
- EllaOne® tablets containing 30 mg ulipristal acetate and therapeutically indicated for emergency contraception (for birth control). It is used within 5 days after unprotected intercourse or failure of primary contraceptive measure.
National health authorities across the globe and marketing authorization holders (MAH) for Esmya® product has withdrawn ulipristal acetate 5 mg (Esmya®) due to potential serious liver injury and liver failure requiring transplantations associated with the use of ulipristal acetate 5 mg.
Esmya® Approval in EU & United States:
- In May 2009, this medicine was granted marketing authorization by European medicines agency (EMA) to market in the region of European union (EU).
- In August 2010, United States Food and Drug Administration (USFDA) granted approval for this medicine to market in US.
Identification of safety concerns:
In 2018, case reports of Esmya® were received pertaining to the serious liver injury associated with ulipristal acetate. There were eight cases reported with “possible” causal relationship between serious liver injury and ulipristal acetate 5 mg and four cases of liver failure leading to liver transplantation. On 31 May 2018, EMA recommended new measures for minimizing this risk based on the review of scientific evidence by pharmacovigilance risk assessment committee (PRAC). Listed below risk minimizing measures (RMM) highlighted in the Direct Healthcare Professional Communication (DHPC) for safe and effective use of Esmya®.
- Contraindication: Contraindication of Esmya® use in women with underlying liver disease/disorder.
- Restricted use: Using Esmya® only in women who are not eligible for surgical treatment. (Esmya continues to be indicated for one course (lasting up to 3 months) of pre-operative treatment for moderate to severe symptoms of uterine fibroids in adult women of reproductive age).
- Monitoring Liver functions tests: Conducting liver tests before, during and after discontinuation of treatment with Esmya® (2-4 weeks after stopping treatment). Esmya should not be given if levels of alanine transaminase (ALT) or aspartate aminotransferase (AST) are more than 2 times the upper limit of normal (ULN).
- Treatment discontinuation: Stopping treatment in patients with ALT or AST levels more than 3 times ULN.
- Safety communication card: A special card to patients to inform/educate about the need of liver function monitoring and to communicate with their respective physician or pharmacist for any potential symptoms of liver injury (tiredness, yellowing of the skin, darkening of the urine, nausea, and vomiting).
Revocation of marketing authorization for ulipristal acetate 5 mg:
On 13 Mar 2020, EMA’s PRAC commenced a second review of safety data for ulipristal acetate as per the request from European commission due to identification of new case reports of serious liver injury and liver transplantations in spite of adherence to the risk minimizing measures implemented in 2018, There were approximately 900,000 patients treated with ulipristal acetate for uterine fibroids since its authorisation in 2012. At that time of ongoing safety review, PRAC recommended suspension of ulipristal acetate intended for uterine fibroids. In April 2020, Esmya products had been recalled from the market in response to these new safety concerns of liver injury risk highlighted by EMA.
The scientific review by PRAC team confirmed the occurrence of liver injury and the need to liver transplantations due to Esmya and generic ulipristal acetate medicines. Based on the available safety evidence from case reports of serious liver injury, PRAC concluded that risks of these medicines outweighed the anticipated benefits. On 04 Sep 2020, due to this unfavorable benefit-risk profile, PRAC recommended revoking marketing authorization for ulipristal acetate, 5 mg intended for the treatment of uterine fibroids to prevent marketing of these medicines in the EU region. However, this recommendation is not applicable for ulipristal acetate intended for emergency contraceptive in single dose (EllaOne® 30 mg), since there were no case reports received pertaining to liver injury association with EllaOne® medicine.
Drug Withdrawal from market:
On 30 Sep 2020, Health Canada announced voluntary withdrawal of FIBRISTAL (ulipristal acetate tablets, 5 mg) in Canada from its MAH – Allergan Inc due to risk of drug-induced liver injury.
On 09 Oct 2020, Health Science Authority (HSA) – regulatory authority of Singapore published notification pertaining to voluntary withdrawal of Esmya tablet 5 mg by MAH – Zuellig Pharma Pte Ltd. Esmya is licensed to market in Singapore since Nov 2014. In March 2020, HSA temporarily suspended the use of this product in the country (as a precautionary measure) owing to the ongoing concern for international case reports on serious liver injury and transplantations attributed to ulipristal acetate tablets, 5 mg. HSA stated that “the withdrawal does not affect Ella® (ulipristal acetate) Tablet 30mg (Hyphens Pharma Pte Ltd) registered for use as an emergency contraception, as there is no concern about liver injury with this product.”
On 14 Dec 2020, National Pharmaceutical Regulatory Agency (NPRA), regulatory body in Malaysia notified healthcare professionals about the withdrawal of Esmya (ulipristal acetate 5 mg) by MAH – Zuellig Pharma Sdn. Bhd. in Malaysia and worldwide.
Every medicinal product has both benefits and risks. Medicines are authorized to market based on the favourable benefit-risk profile anticipated at the time of regulatory approval/entry into market. However, the safety profile of medicine is continuously updated owing to the emerging safety data from the postmarketing experience. If the rate of reporting of suspected adverse drug reactions (ADR) from public is line with the actual occurrence of ADRs, the time lapse for taking regulatory action can be reduced and thereby improving patient safety.
All health care professionals and consumers of pharmaceutical medicinal products are encouraged to be aware of this fact and observe/monitor for any possible adverse events, reactions, medication errors, or quality complaints of medicinal products and report the same to your respective national health authority.
This would accumulate safety evidence for medicinal products which in turn help health authorities to take regulatory actions at the earliest possibility for a better patient safety and overall public health.